Short-term activation induces multifunctional dendritic cells that generate potent antitumor T-cell responses in vivo.
Dendritic cell (DC) vaccines have emerged as a promising strategy to induce antitumoral cytotoxic T cells for the immunotherapy of cancer. The maturation state of DC is of critical importance for the success of vaccination, but the most effective mode of maturation is still a matter of debate. Whereas immature DC carry the risk of inducing tolerance, extensive stimulation of DC may lead to DC unresponsiveness and exhaustion. In this study, we investigated how short-term versus long-term DC activation with a Toll-like receptor 9 agonist influences DC phenotype and function. Murine DC were generated in the presence of the hematopoietic factor Flt3L (FL-DC) to obtain both myeloid and plasmacytoid DC subsets. Short activation of FL-DC for as little as 4 h induced fully functional DC that rapidly secreted IL-12p70 and IFN-alpha, expressed high levels of costimulatory and MHC molecules and efficiently presented antigen to CD4 and CD8 T cells. Furthermore, short-term activated FL-DC overcame immune suppression by regulatory T cells and acquired high migratory potential toward the chemokine CCL21 necessary for DC recruitment to lymph nodes. In addition, vaccination with short-term activated DC induced a strong cytotoxic T-cell response in vivo and led to the eradication of tumors. Thus, short-term activation of DC generates fully functional DC for tumor immunotherapy. These results may guide the design of new protocols for DC generation in order to develop more efficient DC-based tumor vaccines.
Wurzenberger
Cornelia
C
Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University of Munich, Munich, Germany.
Koelzer
Viktor H
VH
Schreiber
Susanne
S
Anz
David
D
Vollmar
Angelika M
AM
Schnurr
Max
M
Endres
Stefan
S
Bourquin
Carole
C
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007114:Immunization; D008213:Lymphocyte Activation / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism
D016207:Cytokines; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; C084881:flt3 ligand protein